Fat accumulation-modulating compounds

Abstract

The present invention pertains to compounds effective at modulating fatty acid or triglyceride accumulation by fat cells, such compounds having therapeutic potential as regulators of body mass and for the treatment of overweight individuals, obesity, and metabolic disorders. Featured compounds are those having the structure set forth and exemplified herein: wherein Ar is a substituted or unsubstituted phenyl group; R is a hydrogen or C 1-6 alkyl group; and P is a substituted or unsubstituted nitrogen-containing heteroaryl group; said compound having the property of modulating the accumulation of fatty acids by cells. Therapeutic methods and pharmaceutical compositions featuring these compounds are also provided.

We claim:  
     
         1 . A method of modulating the accumulation of a fatty acid or triglyceride in a cell, comprising a step of contacting said cell with a compound, wherein said compound is selected according to the following formula:  
       
         
           
           
               
               
           
         
         Ar is a substituted or unsubstituted phenyl group;  
         R is a hydrogen or C 1-6  alkyl group; and  
         P is a substituted or unsubstituted nitrogen-containing aryl group group; said compound having the property of modulating the accumulation of fatty acids by cells.  
       
     
     
         2 . The method according to  claim 1 , wherein Ar is  
       
         
           
           
               
               
           
         
         p is an integer from zero to five inclusive; and  
         X is an alkyl, alkenyl, alkynyl, aryl, (CR′R″) 0-3 NR′R″, (CR′R″) 0-3 CN, NO 2 , halogen, (CR′R″) 0-3 C(halogen) 3 , (CR′R″) 0-3 CH(halogen) 2 , (CR′R″) 0-3 CH 2 (halogen), (CR′R″) 0-3 CONR′R″, (CR′R″) 0-3 S(O) 1-2 NR′R″, (CR′R″) 0-3 CHO, (CR′R″) 0-3 O(CR′R″) 0-3 H, (CR′R″) 0-3 S(O) 0-2 R′, (CR′R″) 0-3 O(CR′R″) 0-3 H, (CR′R″) 0-3 COR′, (CR′R″) 0-3 CO 2 R′, or (CR′R″) 0-3 OR′ group; wherein each R′ and R″ are each independently hydrogen, a C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, or aryl group, or R′ and R″ taken together are a benzylidene group or a —(CH 2 ) 2 O(CH 2 ) 2 — group.  
       
     
     
         3 . The method according to  claim 2 , wherein X is a halogen, C(halogen) 3 , CH(halogen) 2 , CH 2 (halogen), alkyl, or nitro group.  
     
     
         4 . The method according to  claim 2 , wherein X is CF 3 , CCl 3 , CHF 2 , CHCl 2 , F, Cl, Br, I, NO 2 , or an n-alkyl group, and p is 2.  
     
     
         5 . The method according to  claim 2 , wherein X is CF 3 , Cl, n-alkyl, or NO 2 .  
     
     
         6 . The method according to  claim 2 , wherein X is a o-Cl, o-CF 3 , o-F, o-Br, o-I, m-NO 2 , m-CF 3 , or m-F group.  
     
     
         7 . The method according to  claim 2 , wherein p is 2 and X is o-Cl or m-NO 2 .  
     
     
         8 . The method according to  claim 1 , wherein P is  
       
         
           
           
               
               
           
         
         q is an integer from zero to five inclusive; and  
         Y is an alkyl, alkenyl, alkynyl, aryl, (CR′R″) 0-3 NR′R″, (CR′R″) 0-3 CN, NO 2 , halogen, (CR′R″) 0-3 C(halogen) 3 , (CR′R″) 0-3 CH(halogen) 2 , (CR′R″) 0-3 CH 2 (halogen), (CR′R″) 0-3 CONR′R″, (CR′R″) 0-3 S(O) 1-2 NR′R″, (CR′R″) 0-3 CHO, (CR′R″) 0-3 O(CR′R″) 0-3 H, (CR′R″) 0-3 S(O) 0-2 R′, (CR′R″) 0-3 O(CR′R″) 0-3 H, (CR′R″) 0-3 COR′, (CR′R″) 0-3 CO 2 R′, or (CR′R″) 0-3 OR′ group; wherein each R′ and R″ are each independently hydrogen, a C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, or aryl group, or R′ and R″ taken together are a benzylidene group or a —(CH 2 ) 2 O(CH 2 ) 2 — group.  
       
     
     
         9 . The method according to  claim 1 , wherein P is  
       
         
           
           
               
               
           
         
         r is is an integer from zero to two inclusive; and  
         Y is an alkyl, alkenyl, alkynyl, aryl, (CR′R″) 0-3 NR′R″, (CR′R″) 0-3 CN, NO 2 , halogen, (CR′R″) 0-3 C(halogen) 3 , (CR′R″) 0-3 CH(halogen) 2 , (CR′R″) 0-3 CH 2 (halogen), (CR′R″) 0-3 CONR′R″, (CR′R″) 0-3 S(O) 1-2 NR′R″, (CR′R″) 0-3 CHO, (CR′R″) 0-3 O(CR′R″) 0-3 H, (CR′R″) 0-3 S(O) 0-2 R′, (CR′R″) 0-3 O(CR′R″) 0-3 H, (CR′R″) 0-3 COR′, (CR′R″) 0-3 CO 2 R′, or (CR′R″) 0-3 OR′ group; wherein each R′ and R″ are each independently hydrogen, a C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, or aryl group, or R′ and R″ taken together are a benzylidene group or a —(CH 2 ) 2 O(CH 2 ) 2 — group.  
       
     
     
         10 . The method according to  claim 8 , wherein said alkyl group is an n-alkyl or iso-alkyl group.  
     
     
         11 . The method according to  claim 8 , wherein said alkyl group has one to six carbon atoms.  
     
     
         12 . The method according to  claim 8 , wherein q is zero.  
     
     
         13 . The method according to  claim 9 , wherein r is one.  
     
     
         14 . The method according to  claim 1 , wherein R is a hydrogen or methyl group.  
     
     
         15 . The method according to  claim 1 , wherein R is a hydrogen.  
     
     
         16 . The method of  claim 1 , wherein the said compound is 2-chloro-5-nitro-N-pyridin-4-yl-benzamide, 2-chloro-N-(5-methyl-isoxazol-3-yl)-5-nitro-benzamide, or 2-chloro-5-nitro-N-pyridin-3-yl-benzamide.  
     
     
         17 . A pharmaceutical composition for use in the method of  claim 1 .  
     
     
         18 . A prodrug pharmaceutical composition for use in the method of  claim 1 .  
     
     
         19 . The method of  claim 1 , wherein said modulating property is an increase in the accumulation of fatty acids by cells.  
     
     
         20 . The method of  claim 1 , wherein said modulating property is a decrease in the accumulation of fatty acids by cells.  
     
     
         21 . The method according to  claim 1 , wherein said modulating property is an increase in the accumulation of fatty acids or triglycerides by cells.  
     
     
         22 . The method according to  claim 1 , wherein said modulating property is a decrease in the accumulation of fatty acids or triglycerides by cells.  
     
     
         23 . The method according to  claim 1 , wherein modulation of said fatty acid or triglyceride uptake is a means of treating or preventing a disease or condition in a subject.  
     
     
         24 . The method according to  claim 23 , wherein said subject is affected with said disease or condition, has a susceptibility thereto, or has a medical history thereof.  
     
     
         25 . The method according to  claim 23 , wherein said subject is a human.  
     
     
         26 . The method according to  claim 25 , wherein said subject is overweight.  
     
     
         27 . The method according to  claim 25 , wherein said subject is underweight.  
     
     
         28 . The method according to  claim 25 , wherein said subject is obese.  
     
     
         29 . The method according to  claim 25 , wherein said subject has a Body Mass Index of less than about 25.  
     
     
         30 . The method according to  claim 25 , wherein said subject has a Body Mass Index of less than about 20.  
     
     
         31 . The method according to  claim 25 , wherein said subject has a Body Mass Index of less than about 18.  
     
     
         32 . The method according to  claim 25 , wherein said subject has a Body Mass Index of greater than about 20.  
     
     
         33 . The method according to  claim 25 , wherein said subject has a Body Mass Index of greater than about 25.  
     
     
         34 . The method according to  claim 25 , wherein said subject has a Body Mass Index of greater than about 30.  
     
     
         35 . The method according to  claim 25 , wherein said subject has a Body Mass Index of greater than about 32.  
     
     
         36 . The method according to  claim 25 , wherein said subject has a Body Mass Index of greater than about 34.  
     
     
         37 . The method according to  claim 25 , wherein said subject has a Body Mass Index of greater than about 36.  
     
     
         38 . The method according to  claim 25 , wherein said subject has a Body Mass Index of greater than about 38.  
     
     
         39 . The method according to  claim 25 , wherein said subject has a Body Mass Index of greater than about 40.  
     
     
         40 . The method according to  claim 24 , wherein said disease or condition is cancer, AIDS, diabetes, coronary disease, lipodystrophy, hypertension, cachexia, anorexia nervosa, bulemia nervosa, hyperinsulinemia, stroke, congestive heart failure, gall stones, gout, hyperlipiedemia, hypercholesterolemia, atherosclerosis or arteriosclerosis, or metabolic syndrome; a susceptibility thereto, a medical history thereof, or a pathological consequence thereof.  
     
     
         41 . The method of according to  claim 23 , wherein said compound is administered with a suitable pharmaceutical carrier.  
     
     
         42 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1  in combination with a second agent.  
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein said second agent is a weight-reducing or appetite suppressing agent.  
     
     
         44 . The pharmaceutical composition of  claim 42 , wherein said second agent is a chemotherapeutic agent.  
     
     
         45 . The pharmaceutical composition according to  claim 43 , wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier.  
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein said effective amount is effective to treat a lipid metabolism or uptake disorder.  
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein said effective amount is effective to treat obesity.  
     
     
         48 . A packaged composition for treatment of a disease or condition with any compound according to  claim 46 , comprising said compound and directions for using said compound for treating said disease according to said method.  
     
     
         49 . The packaged composition of  claim 48 , further comprising a pharmaceutically acceptable carrier.  
     
     
         50 . The packaged composition of  claim 48 , wherein said disease cancer, AIDS, diabetes, coronary disease, lipodystrophy, hypertension, cachexia, anorexia nervosa, bulemia nervosa, hyperinsulinemia, stroke, congestive heart failure, gall stones, gout, hyperlipiedemia, hypercholesterolemia, atherosclerosis or arteriosclerosis, or metabolic syndrome.  
     
     
         51 . The packaged composition of  claim 48 , further comprising a second agent.  
     
     
         52 . The packaged composition of  claim 51 , wherein said second agent is a weight-reducing or appetite suppressing agent.  
     
     
         53 . The method according to  claim 1 , wherein said cell is an adipocyte or preadipocyte.  
     
     
         54 . The method according to  claim 1 , wherein said cell is subcutaneous.  
     
     
         55 . The method according to  claim 1 , wherein said cell is visceral.  
     
     
         56 . The method according to  claim 23 , wherein said subject is a companion animal.  
     
     
         57 . The method according to  claim 56 , wherein said companion animal is a dog or cat.  
     
     
         58 . The method according to  claim 1 , wherein modulation of said fatty acid or triglyceride accumulation is a means of producing leaner or fatter livestock.  
     
     
         59 . The method according to  claim 58 , wherein said livestock are pigs, cows, lamb, sheep, or horses.  
     
     
         60 . An animal feedstock comprising a chemical according to  claim 1.